Heart failure (HF) is a syndrome or clinical condition resulting from failure of the heart to maintain adequate circulation of blood. It can be chronic or acute, and has many etiologies including ischemic infarction or myocardial infarction.
According to the American Heart Association, the total direct and indirect costs for HF in the US are estimated at $27.9 billion in 2005. The HF market has been devoid of novel drugs on the market for some time partially because drug development in the HF arena has one of the highest late stage failure rates. However, HF prevalence and incidence are increasing as a result of an aging population and increasing survival in the underlying cardiovascular disease patient base. This has resulted in an increased demand for new treatments. The US HF market is expected to grow from $1.33 billion in 2004 to $4.33 billion by 2011. Marketed products include angiotensin converting enzyme (ACE) inhibitors such as Vasotec and Altace, β-adrenergic blockers (ARBs) such as Troprol and Coreg, nitric oxide enhancing therapy (BiDil), angiotensin II receptor blockers such as Diovan and Atacand, mineralocorticoid receptor antagonists such as Inspra, and recombinant human B-type natriuretic peptide (Natrecor). There are also generic inotropes, vasodilators and diuretics. Emerging therapies include statins, inotropes with calcium sensitizer and PDE properties, recombinant erythropoietic protein, α-human natriuretic peptide, vasopressin antagonists, advanced glycation end-product (AGE) crosslink breakers, and xanthene oxidase inhibitors, among others.
In the US, there are about 5 million heart failure patients and more that 285,000 deaths occur annually from this disease (American Heart Association, Heart Disease and Stroke Statistics, 2006 Update, Dallas, Tex.). The number of patients is on the rise and is expected to reach 11.5 million in 2011 (Frost & Sullivan, U.S. Heart Failure Therapeutics Markets, F666-52, 2006; http://www.frost.com). Approximately 1.6 million patients have New York Heart Association Class III or IV HF encompassing the population with moderate to severe symptoms. These syndromes typically progress from Class III to IV over 3 to 10 years where the patients may be treated with optimal pharmacological therapy such as β-blockers, angiotensin II receptor type 1 blockers, angiotensin I converting enzyme inhibitors, calcium channel blockers, and vasodilators. As additional symptoms occur, patients may require medical devices such as implantable pacemakers or defibrillators and possibly left ventricular assist devices (LVADs). With the possible exception of LVADs, these therapies prolong life but do not stop or reverse the deterioration of heart function. In the mid- and end-stages of this disease, patients are frequently hospitalized for shortness of breath with dangerously low left ventricular ejection fraction (acute decompensation in patients with chronic HF or acute HF). These patients require IV inotropes to increase contractility of the heart muscle, IV diuretics to decrease fluid burden, and IV vasodilators to decrease peripheral vascular resistance (ACC 2005). However, patients are discharged with signs and symptoms of congestive HF and within 2 months after discharge, the readmission rate is about 30% and the mortality rate is 10%. See, e.g., Gheorghiade, M. et al., Early Management of Acute Heart Failure Syndromes, in Cardiovascular Emergencies, 2006, Omni, Atlanta, Mar. 11, 2006. Thus, there is an immediate and critical need for better therapies to treat acute HF.
Heart failure may be manifested by cardiac muscle dysfunction, e.g., abnormal contraction of heart muscle such as diastolic or systolic dysfunction. While several therapies are available to treat abnormal contraction, there are currently no therapies that target diastolic dysfunction of heart muscle seen in approximately 2.3 million patients. Despite various etiologies of HF, its syndromes are highly related and systolic and diastolic dysfunctions coexist in most patients. See, e.g., Dyer, G. S. M. et al., Heart Failure, in Pathophysiology of Heart Disease (L. S. Lilly ed.), Lippincott Williams & Wilkins, Baltimore, Md., 2003, p. 234. Diastolic dysfunction results from compromised ventricular heart relaxation (filling) in the presence of abnormal heart contraction and ejection fraction. See, e.g., Zile, M. R. et al., Circulation, 2002, 105:1387-1393. Diastolic HF DHF) is most often associated with coronary artery disease, hypertension, aging and infiltrative cardiomyopathy. Currently there are no consensus guidelines for the treatment of chronic diastolic dysfunction as compared with the ACC/AHA treatment guidelines for systolic-related HF.
Heart dysfunction may be associated with loss or lack of dystrophin in the cardiac muscle cell membrane (Takahashi, M. et al., Eur. J. Pharmacol., 2005, 522: 84-93; Yasuda, S. et al., Supra; Kaprielian, R. R. et al., Circulation, 2000, 101: 2586-2594; Toyo-Oka, T. et al., Proc. Natl. Acad. Sci. USA, 2004, 101: 7381-7385). Dystrophin is a structural protein that participates in cellular organization in muscle cells and promotes both myofibril and sarcolemma (muscle cell membrane) stability. See, e.g., Kaprielian, R. R. et al., Circulation, 2000, 101: 2586-2594. Genetic dystrophin deficiency or abnormal dystrophin level are the underlying cause of Duchenne muscular dystrophy (MD) and Becker's muscular dystrophy (BMD), respectively. Cardiac disease in both DMD and BMD manifests as dilated cardiomyopathy (DCM), ardiac arrhythmia, or both. It is seen in young patients with an incidence of 26% by the age of 6 and causes death of these patients typically in their early to mid 20s. About 20% of DMD patients and 50% of BMD patients die from HF. Female carriers of DMD or BMD are also at risk for cardiomyopathy. For carriers the age of onset is unclear but is thought to be in the adult years. Cardiac involvement ranges from asymptomatic to severe HF. See, e.g., American Academy of Pediatrics, Clinical Report, Pediatrics, 2005, 116:1569-1573.
Dystrophin levels in the muscle cell membrane can also be influenced by environmental factors such as pathological stresses including catecholamine administration, coronary ligation resulting in acute myocardial ischemia, and in chronic HF after myocardial infarction (MI). The increase in intracellular calcium (Ca+2) in HF subsequent to MI is well established with changes in calcium handling such as impaired removal of cytosolic calcium by the sarcoplasmic reticulum (SR), ryanodine receptor leakage, decreased activity of the sodium/calcium exchanger, and increased activity of phospholamban accompanying impairment of cardiac relaxation and systolic function. See, e.g., Morgan, J. P. et al., Circulation, 1990, 81:III21-III32; Iwanaga, Y. et al., J. Clin Invest., 2004, 113:727-736; Zhang, X.-Q. et al., J. Appl. Physiol., 2002, 93:1925-1931; Wehrens, X. H. et al., Proc. Natl. Acad. Sci. USA, 2006, 103:511-518; Angeja, B. G. et al., Circulation, 2003, 107:659-663. These mechanisms may work to increase calcium initially leading to activation of calpains (calcium-activated proteases) and remodeling pathways. Activation of calpains could lead to initial loss of dystrophin from the membrane, causing it to become unstable and susceptible to contractile stress. The loss of dystrophin and dystrophin-associated proteins from the membranes of cardiomyocytes from HF patients and animal HF models is well documented. See, e.g., Kawada, T. et al., Pharmacol. Therap., 2005, 107: 31-43; Kaprielian, R. R. et al., Circulation, 2000, 101:2586-2594). These proteins form complexes that provide mechanical resistance to overexpansion of the sarcolemma. Loss of these proteins is associated with an increase in the number of cardiomyocytes taking up the membrane impermeable dye Evans Blue. See, e.g., Takahashi, M. et al, Eur. J. Pharmacol., 2005, 522:84-93.
Further, an increase in calpains was demonstrated in models of myocarditis where loss of dystrophin correlates with functional deficit (Lee, G.-H. et al., Circ. Res., 2000, 87:489-495).
Tears in the sarcolemma have been shown to be a conduit for calcium to enter the cell and increase intracellular calcium. It has been proposed that a vicious cycle exists where stresses that cause a sustained increase in intracellular calcium, either directly or indirectly, lead to advanced HF. See, e.g., Kawada, T. et al., Pharmacol. Therap., 2005, 107:31-43. In this cycle, the increased sustained calcium activates calpains which, among other things, cleave dystrophin. This leads to more membrane instability, more tears and more calcium. As the remaining cardiomyocytes are stressed because of increased work demand, they too enter this cycle.
ACE inhibitors and ARBs are drugs that have been shown to improve cardiac hemodynamics and survival in patients with heart failure. In the rat MI model of heart failure, both of these agents have been shown to prevent a decrease in the level of dystrophin from the membrane fraction of cardiac muscle cells, after MI, presumably by decreasing the total calpain content. This effect was seen when the rats were treated with these agents chronically from 2-8 weeks post infarction. See Takahashi, M. et al., Cardiovasc. Res. 2005, 65: 356-365.
It has also been established that sustained increases in intracellular calcium result in the activation of signaling pathways, which subsequently result in maladaptive remodeling of the heart contributing to the functional problems. See, e.g., Molkentin, J. D. et al., Cell, 1998, 93: 215-228; Wilkins, B. J. et al., Circulation Research, 2004, 94:110-8).
Taken together, it appears that dystrophin loss and membrane instability contribute to cardiac muscle dysfunction in HF.